The present invention relates to novel biphenylyl propionic acid derivatives. More particularly, the present invention relates to biphenylylpropionic acid derivatives having the formula (I): ##STR4## wherein R is an alkylcarbonyloxyalkyl group or an alkenylcarbonyloxyalkyl group having the formula (II): ##STR5## wherein R.sup.1 is a lower alkyl group having 1 to 5 carbon atoms and R.sup.2 is an alkyl group having 1 to 15 carbon atoms or an alkenyl group having 2 to 8 carbon atoms, or a lactone having the formula (III): ##STR6## wherein R.sup.3 and R.sup.4 are hydrogen atom or a lower alkyl group having 1 to 2 carbon atoms, and n is an integer of 1 or 2,
a process for preparing the same and a pharmaceutical composition containing the same as an effective ingredient.
It is known that 2-(2-fluoro-4-biphenylyl)-propionic acid (hereinafter referred to as "FP") has strong anti-inflammatory, analgesic and antipyretic activities. However, the formulation form of FP is limited in the form of injection, syrup, or an external preparation such as ophthalmic agent, suppository, cream or plaster because of its irritation. Thus, various modifications are required for a pharmaceutical preparation of FP and the preparation is difficult.
As a result of various studies, the present inventors have now found that a satisfactory drug which cause no irritation, an has excellent pharmacological effect several times higher than that of FP and fewer side effects. That is, the compound (I) of the present invention prepared from FP by esterifying cause no irritation. Moreover, the compound (I) is excellent in absorption from mucosa or skin because of its high hydrophobic property Thus, the pharmacological effect of the compound (I) appears rapidly and is increased. On the other hand, when the compound (I) is formulated in combination with an oleaginous base, the pharmacological effect of the compound (I) is increased and prolonged, and the bioavailability of the compound (I) is increased. Further, the compound (I) is hard to bind with plasma proteins because of its physicochemical properties such as no free polar group and solubility in oil. As a result, the tissue distribution and metabolism of the compound (I) after administration are different from those of FP. Accordingly, the concentration of the compound (I) at an inflammatory site is increased to show excellent pharmacological effects.
Though a sustained-release agent is generally utilized in order to prolong a pharmacological effect, the compound (I) of the present invention gains a prolongation of a pharmacological effect by advantageously utilizing a reaction of metabolic enzyme. More particularly, since the compound (I) has diastereomers as a result of having two asymmetric carbon atoms in the molecule, there is evidenced a difference of hydrolyzing rate among the diastereomers when the compound (I) is hydrolyzed by metabolic enzymes in tissues. When measured by gas chromatography, for instance, there appears about a 5-fold difference in the hydrolyzing rate in plasma. Thus, FP being a parent material of the compound (I) is slowly and complementarily released in its physiologically active form in tissues to prolong an effective blood concentration of FP.
Therefore, the compound (I) is excellent as a drug causing no irritation, excellent pharmacological effect, is rapid and long-acting and has a large safety margin.
It is an object of the present invention to provide novel FP derivatives which are useful and characteristic pro-drugs by utilizing advantageously an enzyme reaction. The compounds have excellent anti-inflammatory, analgesic and antipyretic activities, fewer side effects and high safety.
A further object of the invention is to provide a process for preparing FP derivatives.
Another object of the invention is to provide a pharmaceutical composition containing FP derivatives as effective ingredients.
These and other objects of the invention will become apparent from the description hereinafter.